1. Field of the Invention
The invention relates to a process for the preparation of 1,2,4-substituted (and 2,4(5)-substituted) imidazole derivatives. The invention also relates to the use of such derivatives for a preferred preparation of substituted aminoalkylimidazole derivatives; examples of such compounds are disclosed in U.S. Pat. No. 4,829,065. The invention also relates to novel substituted aminoalkylimidazole derivatives, which are useful for treating ischaemia, particularly including disease states such as stroke.
2. Background to the Invention
Existing regioselective syntheses of 2,4(5)-substituted and 1,2,4-substituted imidazole derivatives of Formula (I) require several steps, are difficult to carry out, and give low overall yields; see, for example, Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky, Volume 5, page 457 (1984).
Processes for the preparation of compounds of Formula (II) where --NR.sup.6 R.sup.7 represents a piperazine derivative are disclosed in U.S. Pat. Nos. 4,829,065 and 5,043,447. The '065 patent initially requires the preparation of an imidazole substituted at the 4(5) -position by -CH.sub.2 O , followed by a two-step conversion to the desired product. The '447 patent discloses a more efficient process for the preparation of the desired substituted imidazolylalkylpiperazine derivatives, in that once the starting materials have been prepared, the process can be carried out in a single reaction vessel. However, the preparation of a potentially unstable iminoether hydrochloride is required initially, which is then converted to an amidine and reacted with a costly 1,2-dione to prepare the imidazole intermediate necessary for reaction with a substituted piperazine. Additionally, this process works poorly where the amidine is a benzamidine in which the phenyl possesses an electron withdrawing group.
The present process provides for an improved preparation of 2,4(5)-substituted and 1,2,4-substituted imidazole derivatives of Formula (I), and aminoalkylimidazole derivatives of Formula (II). The invention provides most particularly for a one-step process for the large-scale production of compounds of Formula (I), and a two-step process for the large-scale production of (II). These processes have surprising advantages over previously disclosed processes in that they do not require the use of potentially unstable imidoesters, iminoethers, chloroimidates, or the like, and the use of ammonia and concentrated hydrochloric acid is also avoided. Additionally, the intermediate compounds for the preparation of compounds of Formula (I) do not need to be isolated or purified during the process, and consequently the synthesis can be conducted in a single reaction vessel. Further, the compounds of Formula (I) can be prepared by cyclizing the alkynyl imine precursor in the absence of a catalyst, in which case compound (I) generally crystallizes out from the reaction mixture after the reaction is complete, in good yield and in high purity, such that there is no need for further purification. Alternatively, the compounds of Formula (I) can be prepared by cyclizing the alkynyl imine precursor in the presence of a catalyst, in which case the reaction time for completion of the reaction is considerably shortened.